Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

doi:10.6023/cjoc202405036

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (11): 3476-3489.DOI: 10.6023/cjoc202405036 Previous Articles Next Articles

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烷基共轭二烯基二酸作为新型ACLY抑制剂的发现

程婷婷^†,a^,^b, 宋高磊^†,a, 成龙^†,a^,^b, 王凡^c, 孙新宇^a, 谢治富^a, 张梅^a, 张仰明^d, 李静雅^a^,^b^,^c^,^*(), 南发俊^a^,^b^,^*()

a 中国科学院上海药物研究所新药研究国家重点实验室上海 201203
b 中国科学院大学北京 100049
c 南京中医药大学新中药学院南京 210023
d 博骥源(上海)生物医药有限公司上海 201203

收稿日期:2024-05-27 修回日期:2024-05-30 发布日期:2024-06-07
作者简介:
†共同第一作者
基金资助:
国家自然科学基金(82170872); 上海市科委生物医药科技支撑专项(20S11903400); 上海市科委自然科学基金(21ZR1475300)

Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

Tingting Cheng^†,a^,^b, Gaolei Song^†,a, Long Cheng^†,a^,^b, Fan Wang^c, Xinyu Sun^a, Zhifu Xie^a, Mei Zhang^a, Yangming Zhang^d, Jingya Li^a^,^b^,^c,*(), Fajun Nan^a^,^b,*()

a State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
b University of Chinese Academy of Sciences, Beijing 100049
c School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023
d Burgeon Therapeutics Co., Ltd, Shanghai 201203

Received:2024-05-27 Revised:2024-05-30 Published:2024-06-07
Contact: *E-mail:jyli@simm.ac.cn; fjnan@simm.ac.cn
About author:
†The authors contributed equally to this work.
Supported by:
National Natural Science Foundation of China(82170872); Medical Guidance Project of Shanghai Science and Technology Commission(20S11903400); Natural Science Foundation of Shanghai Science and Technology Innovation Action Plan(21ZR1475300)

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Abstract

Adenosine triphosphate (ATP)-citrate lyase (ACLY) converts cytosolic citrate from the tricarboxylic acid cycle (TCA cycle) into acetyl coenzyme A (acetyl-CoA), which is a building block for cholesterol and fatty acid synthesis. Abnormally high expression of ACLY is associated with multiple metabolic diseases including dyslipidemia, atherosclerosis and non-alcoholic steatohepatitis (NASH), making ACLY an appealing target. In previous work, 326Eb was discovered, featuring an alkenyl dicarboxylic acid scaffold as a novel ACLY inhibitor. 326E can be potentially used to treat hypercholesterolemia and is currently undergoing phase II clinical trials. In this study, a series of diacids containing conjugated diene were developed based on impurities in manufacturing process of 326E in good manufacturing practice of medical products (GMP) condition, which represented a unique structural type different from known ACLY inhibitors. Among synthesized all eight possible isomers, compounds 43ZZ and 52EE exhibited significant inhibitory effect on de novo lipogenesis and gluconeogenesis in vitro and 43ZZ showed favorable pharmacokinetics. Furthermore, oral administration of 43ZZ and 52EE demonstrated a marked reduction of hepatic lipogenesis, along with lowered plasma levels of triglyceride and cholesterol, thereby confirming that these diene diacids as novel ACLY inhibitors have therapeutic potential for hyperlipidemia.

Key words: metabolic diseases, ATP-citrate lyase (ACLY), lipogenesis, ACLY inhibitors, dienyldicarboxylic acid

Cite this article

Tingting Cheng, Gaolei Song, Long Cheng, Fan Wang, Xinyu Sun, Zhifu Xie, Mei Zhang, Yangming Zhang, Jingya Li, Fajun Nan. Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors[J]. Chinese Journal of Organic Chemistry, 2024, 44(11): 3476-3489.

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Fig. & Tab. 9

Figure 1. Structures of representative ACLY inhibitors

Figure 2. Possible pathway of Imp9 generation

Figure 3. Structures of the 324 series

Scheme 1. Synthesis of the 324 series Reaction conditions: (a) TMSCl, n-BuLi, tetrahydrofuran (THF), －78 ℃ to r.t.; (b) m=2~4, PPh3, N-bromo-succinimide (NBS), dichloromethane (DCM), －78 ℃ to r.t.; m=1, PPh3, imidazole, DCM, 0 ℃ to r.t.; (c) ethyl isobutyrate, lithium diisopropylamide (LDA), THF, －78 ℃ to r.t.; (d) tetrabutylammoniumfluoride (TBAF), THF, r.t.; (e) I2, diisobutylaluminumhydride (DIBAL-H), Cp2ZrCl2, THF, 0 ℃; (f) pinacolbrane, Cp2ZrHCl, NEt3, 60 ℃; (g) I2, InCl3, DIBAL-H, BEt3, THF, －78 ℃; (h) XPhos Pd G2, Cs2CO3, dimethyl sulfoxide (DMSO), 50 ℃; (i) NaOH, H2O, EtOH, 90 ℃; (j) Pd(PPh3)2Cl2, CuI, NEt3, r.t.; (k) H2, Ni(OAc)2?4H2O, NaBH4, ethylene diamine, EtOH, r.t.

Figure 4. 324 series reduce lipogenesis and gluconeogenesis in vitro (A) 324 series incubation for 4 h inhibit lipogenesis traced by 14C-acetate (0.1 μCi/well) in primary hepatocytes (n=3~4). (B~C) Dose-dependent inhibition for lipogenesis of compound 43ZZ (B) and 52EE (C) in primary hepatocytes (n=4). (D~E) Representative photographs of 10 mmol/L fructose-induced lipoid accumulation stained by C12-Bodipy after 50 μmol/L 43ZZ and 52EE treatment for 24 h, the quantifications (E) of the C12-Bodipy intensity in D (n=3). (F) Primary mouse hepatocytes were treated with the indicated concentration of 43ZZ and 52EE for 6 h. The rate of gluconeogenesis in the medium induced by pyruvate (2 mmol/L) and lactate (20 mmol/L) was measured (n=4). The content of glucose output after 6 h treatment of 43ZZ, 52EE. Data are mean±SEM; *P<0.05, **P<0.01, ***P<0.001 compared to Ctrl or indicated group.

Scheme 2. Synthesis of 43ZZ-CoA and 52EE-CoA

Figure 5. 43ZZ-CoA and 52EE-CoA are competitive ACLY inhibitors (A) Structures of 43ZZ-CoA and 52EE-CoA. (B~E) Dose-dependent inhibition of purified, recombinant ACLY after incubated with 43ZZ (B), 43ZZ-CoA (C), 52EE (D), 52EE-CoA (E). (F~I) Recombinant human ACLY was incubated with indicated concentrations of 43ZZ-CoA with coenzyme A (F) or citrate (G), 52EE-CoA with coenzyme A (H) or citrate (I). Ki was calculated by Michaelis-Menten kinetic analysis in prism. (J~K) Thermal shift curve and Tm value table on ACLY in the presence of 43ZZ-CoA, 52EE-CoA or substrates (n=2).

Species	Route	Dose/ (mg•kg^－1)	CL/(mL•min^－1•kg^－1)	Vss/(L•kg^－1)	t_1/2/h	T_max/h	c_max/(μg•mL^－1)	AUC_0-_t/ (μg•h^－1•mL^－1)	Bioavailability (F/%)
ICR mice	iv	2	1.58	0.49	6.47	NA	NA	20.61	93.1
ICR mice	po	10	NA	NA	5.39	0.25	37.2	95.94	93.1

Table 1. Preclinical pharmacokinetics of 43ZZ in micea

Figure 6. 43ZZ and 52EE inhibit lipogenesis and hyperlipidemia in vivo (A) Schematic diagram of 43ZZ and 52EE treatment for in vivo lipogenesis model (n=5~6). (B, C) Content of radioactive lipid extracted from liver and blood after 43ZZ and 52EE single dose treatment; CCPM: corrected counts per minute. (D) Table of total cholesterol and triglycerides in lipid lowering model of 43ZZ and 52EE. (E) Percentage reduction in cholesterol and triglycerides after treatment with 43ZZ and 52EE. Data are mean±SEM; *P<0.05, ***P<0.001 compared to Veh.

References 29

[1]	Moore M. C.; Coate K. C.; Winnick J. J.; An Z.; Cherrington A. D. Adv Nutr. 2012, 3, 286.
[2]	Petersen M. C.; Vatner D. F.; Shulman G. I. Nat. Rev. Endocrinol. 2017, 13, 572. doi: 10.1038/nrendo.2017.80 pmid: 28731034
[3]	Tan M.; Mosaoa R.; Graham G. T.; Kasprzyk-Pawelec A.; Gadre S.; Parasido E.; Catalina-Rodriguez O.; Foley P.; Giaccone G.; Cheema A.; Kallakury B.; Albanese C.; Yi C.; Avantaggiati M. L. Cell Death Differ. 2020, 27, 2143.
[4]	Wei X.; Schultz K.; Bazilevsky G. A.; Vogt A.; Marmorstein R. Nat. Struct. Mol. Biol. 2020, 27, 33.
[5]	Srere P. A. J. Biol. Chem. 1959, 234, 2544.
[6]	Lau F. D.; Giugliano R. P. JAMA Cardiol. 2023, 8, 879.
[7]	Zaidi N.; Swinnen J. V.; Smans K. Cancer Res. 2012, 72, 3709.
[8]	Granchi C. Eur. J. Med. Chem. 2018, 157, 1276.
[9]	Pinkosky S. L.; Groot P. H. E.; Lalwani N. D. Trends Mol. Med. 2017, 23, 1047. doi: S1471-4914(17)30160-0 pmid: 28993031
[10]	Feng X.-J.; Zhang L.; Xu S.-W.; Shen A.-Z. Prog. Lipid Res. 2020, 77, 101006.
[11]	Morrow M. R.; Batchuluun B.; Wu J.; Ahmadi E.; Leroux J. M.; Mohammadi-Shemirani P.; Desjardins E. M.; Wang Z.; Tsakiridis E. E.; Lavoie D. C. T.; Reihani A.; Smith B. K.; Kwiecien J. M.; Lally J. S. V.; Nero T. L.; Parker M. W.; Ask K.; Scott J. W.; Jiang L.; Paré G.; Pinkosky S. L.; Steinberg G. R. Cell Metab. 2022, 34, 919.
[12]	Liang J.-J.; Zhou X.-F.; Long H.; Li C.-Y.; Wei J.; Yu X.-Q.; Guo Z.-Y.; Zhou Y.-Q.; Deng Z.-S. Bioorg. Chem. 2024, 142, 106933.
[13]	Li J.-J.; Wang H.; Tino J. A.; Robl J. A, Herpin T. F.; Lawrenc R. M.; Biller S.; Jamil H.; Ponticiello R.; Chen L.; Chu C.-H.; Flynn N.; Cheng D.; Zhao R.; Chen B.; Schnur D.; Obermeier M. T.; Sasseville V.; Padmanabha R.; Pike K.; Harrity T. Bioorg. Med. Chem. Lett. 2007, 17, 3208.
[14]	Wei J.; Leit S.; Kuai J.; Therrien E.; Rafi S.; Harwood H. J.; Jr, DeLaBarre B.; Tong L. Nature 2019, 568, 566.
[15]	Gribble A. D.; Ife R. J.; Shaw A.; McNair D.; Novelli C. E.; Bakewell S.; Shah V. P.; Dolle R. E.; Groot P. H.; Pearce N.; Yates J.; Tew D.; Boyd H.; Ashman S.; Eggleston D. S.; Haltiwanger R. C.; Okafo G. J. Med. Chem. 1998, 41, 3582. pmid: 9733484
[16]	Ray K. K.; Bays H. E.; Catapano A. L.; Lalwani N. D.; Bloedon L. T.; Sterling L. R.; Robinson P. L.; Ballantyne C. M.; Trial C. H. N. Engl. J. Med. 2019, 380, 1022.
[17]	Goldberg A. C.; Leiter L. A.; Stroes E. S. G.; Baum S. J.; Hanselman J. C.; Bloedon L. T.; Lalwani N. D.; Patel P. M.; Zhao X.; Duell P. B. JAMA 2019, 322, 1780. doi: 10.1001/jama.2019.16585 pmid: 31714986
[18]	Pinkosky S. L.; Newton R. S.; Day E. A.; Ford R. J.; Lhotak S.; Austin R. C.; Birch C. M.; Smith B. K.; Filippov S.; Groot P. H. E.; Steinberg G. R.; Lalwani N. D. Nat. Commun. 2016, 7, 13457. doi: 10.1038/ncomms13457 pmid: 27892461
[19]	Xie Z.-F.; Zhang M.; Song Q.; Cheng L.; Zhang X.-W.; Song G.-L.; Sun X.-Y.; Gu M.; Zhou C.-D.; Zhang Y.-M.; Zhu K.-X.; Yin J.-P.; Chen X.-Y.; Li J.-Y.; Nan F.-J. Acta. Pharm. Sin. B 2023, 13, 739.
[20]	Song G.-L.; Cao L.; Zhang M.; Yang Y.-R.; Ma J.; Xie Z.-F.; Li J.-Y.; Nan F.-J. Chin. J. Chem. 2022, 40, 2663.
[21]	Wang G.-W.; Mohan S.; Negishi E. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 11344.
[22]	Wang Y. D.; Kimball G.; Prashad A. S.; Wang Y. Tetrahedron Lett. 2005, 46, 8777.
[23]	Ren G.-B.; Wu Y.-K. Tetrahedron 2008, 64, 4408.
[24]	Molander G. A.; Trice S. L.; Kennedy S. M. J. Org. Chem. 2012, 77, 8678. doi: 10.1021/jo301642v pmid: 22994557
[25]	Suh Y. G.; Min K. H.; Lee Y. S.; Seo S. Y.; Kim S. H.; Park H. J. Tetrahedron Lett. 2002, 43, 3825.
[26]	Zhao S.; Jang C.; Liu J.; Uehara K.; Gilbert M.; Izzo L.; Zeng X.; Trefely S.; Fernandez S.; Carrer A.; Miller K. D.; Schug Z. T.; Snyder N. W.; Gade T. P.; Titchenell P. M.; Rabinowitz J. D.; Wellen K. E. Nature 2020, 579, 586.
[27]	Softic S.; Cohen D. E.; Kahn E. R. Dig. Dis. Sci. 2016, 61, 1282.
[28]	Pinkosky S. L.; Filippov S.; Srivastava R. A.; Hanselman J. C.; Bradshaw C. D.; Hurley T. R.; Cramer C. T.; Spahr M. A.; Brant A. F.; Houghton J. L.; Baker C.; Naples M.; Adeli K.; Newton R. S. J. Lipid Res. 2013, 54, 131.
[29]	Li W.-C.; Ralphs K. L.; Tosh D. Methods Mol. Biol. 2010, 633, 185.

烷基共轭二烯基二酸作为新型ACLY抑制剂的发现

Discovery of Alkyl Conjugated Diene Diacids as Novel ACLY Inhibitors

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